Nav1.7 channels, voltage gated sodium channels, are encoded for by the gene SCN9A. These channels are preferentially expressed in peripheral sensory neurons of the dorsal root ganglia, which are involved in the perception of pain.
Mutations in the SCN9A gene have been associated with predispositions to pain hyper- or hypo-sensitivity. For instance, a role for the Nav1.7 channel in pain perception was established by recent clinical gene-linkage analyses that revealed gain-of-function mutations in the SCN9A gene as the etiological basis of inherited pain syndromes such as primary erythermalgia (PE) and paroxysmal extreme pain disorder (PEPD). Alternatively, loss-of-function mutations of the SCN9A gene result in a complete inability of an otherwise healthy individual to sense any form of pain. Moreover, experimentally, a specific deletion of the SCN9A gene in transgenic mice drastically reduces their ability to perceive mechanical, thermal or inflammatory pain. This evidence suggests that increased levels of Nav1.7 channels could enhance pain sensitivity whereas decreased levels of Nav1.7 channels could reduce pain sensitivity.
The foregoing suggests that decreasing Nav1.7 channel levels in peripheral sensory neurons of the dorsal root ganglia could provide an effective pain treatment. This approach could be beneficial due to several drawbacks associated with present pain treatments. For example, current pain therapies include drugs that are non-selective for their targets. This non-selectivity results in side effects involving the central nervous system (CNS). Therefore, more selective treatment options are needed.
One approach to provide local treatments is by reducing the expression and/or inhibiting the function of Nav1.7 channel in the dorsal root ganglia. This reduction can be achieved in several ways, including through the genetic technology, RNA interference (RNAi) or other similar mechanisms. RNA interference allows the selective suppression of the expression of specific proteins, such as the Nav1.7 channels. To understand the potential impact of this technology within the present invention, some background in the art is helpful.
Generally, for a protein, such as the Nav1.7 channel, to exert a biological effect, the cell that will use the protein must create it. To create a protein the cell first makes a copy of the protein's gene sequence in the nucleus of the cell (in this instance, the sequence of the SCN9A gene that encodes for the Nav1.7 channel protein). This copy of the gene sequence that encodes for the protein (called messenger RNA (“mRNA”)) leaves the nucleus and is trafficked to a region of the cell containing ribosomes. Ribosomes read the sequence of the mRNA and create the protein for which it encodes. This process of new protein synthesis is known as translation. A variety of factors affect the rate and efficiency of protein translation. Among the most significant of these factors is the intrinsic stability of the mRNA itself. If the mRNA is degraded quickly within the cell (such as before it reaches a ribosome), it is unable to serve as a template for new protein translation, thus reducing the cell's ability to create the protein for which it encoded.
Based on the foregoing, the technology of RNAi has emerged. RNA interference is, in fact, a naturally-occurring mechanism for suppressing gene expression and subsequent protein translation. RNA interference reduces protein expression by either degrading the mRNA before it can be translated into a protein or by binding the mRNA and directly preventing its translation. This technology provides an avenue to suppress the expression of the SCN9A gene and resulting production of Nav1.7 channels. A reduction in the number of Nav1.7 channels in the peripheral sensory neurons of the dorsal root ganglia could decrease pain sensitivity.